The present invention relates generally to a series of novel small molecules, their synthesis and their use in the treatment of inflammatory disease.
Research spanning the last decade has helped to elucidate the molecular events attending cell-cell interactions in the body, especially those events involved in the movement and activation of cells in the immune system. See generally, Springer, T. Nature, 1990, 346, 425-434. Cell surface proteins, and especially the Cellular Adhesion Molecules (xe2x80x9cCAMsxe2x80x9d) and xe2x80x9cLeukointegrinsxe2x80x9d, including LFA-1, MAC-1 and gp150.95 (referred to in WHO nomenclature as CD18/CD11a, CD 18/CD11b, and CD18/CD11c, respectively) have correspondingly been the subject of pharmaceutical research and development having as its goal the intervention in the processes of leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory component of the inflammatory response, activation of integrins constitutively expressed on leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g., LFA-1) and one or several distinct intercellular adhesion molecules (ICAMS) designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vessel endothelial cell surfaces and on other leukocytes. The interaction of the CAMs with the Leukointegrins is a vital step in the normal functioning of the immune system. Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally Kishimoto, T. K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.
A group of individuals has been identified which lack the appropriate expression of Leukointegrins, a condition termed xe2x80x9cLeukocyte Adhesion Deficiencyxe2x80x9d (Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD18 family. By virtue of the fact that LAD patients who lack CD18 cannot mount an inflammatory response, it is believed that antagonism of CD18, CD11/ICAM interactions will also inhibit an inflammatory response.
It has been demonstrated that the antagonism of the interaction between the CAMs and the Leukointegrins can be realized by agents directed against either component. Specifically, blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1, by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune response inhibited by antibodies to CAMs or Leukointegrins include antigen or mitogen-induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. The relevance of the in vitro studies are supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice (Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greater significance, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37, 992-1004) and antibodies directed against LFA-1 have demonstrated immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A.; et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation, 1991, 52, 291-295).
It has also been demonstrated that a recombinant soluble form of ICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18,CD11/ICAM-1 interactions on cells and shows inhibitory activity in in vitro models of immune response such as the human mixed lymphocyte response, cytotoxic T cell responses and T cell proliferation from diabetic patients in response to islet cells (Becker, J. C.; et al, J. Immunol. 1993, 151, 7224 and Roep, B. O.; et al, Lancet, 1994, 343, 1590).
Thus, the prior art has demonstrated that large protein molecules which antagonize the binding of the CAMs to the Leukointegrins have therapeutic potential in mitigating inflammatory and immunological responses often associated with the pathogenesis of many autoimmune or inflammatory diseases. However proteins have significant deficiencies as therapeutic agents, including the inability to be delivered orally and potential immunoreactivity which limits the utility of theses molecules for chronic administration. Furthermore, protein-based therapeutics are generally expensive to produce.
Several small molecules have been described in the literature which affect the interaction of CAMs and Leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be inhibitory in an in vitro cell binding assay (Musza, L. L.; et al., Tetrahedron, 1994, 50, 11369-11378). One series of molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in a reverse passive Arthus reaction, an induced model of inflammation that is characterized by neutrophil accumulation (Chang, Y. H.; et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another series of molecules was also found to be orally active in a delayed type hypersensitivity reaction in rats (Sanfilippo, P. J.; et al, J. Med. Chem. 1995, 38, 1057-1059). All of these molecules appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other proteins or act intracellularly to inhibit the activation of the Leukointegrins by an unknown mechanism. None of the molecules directly antagonize the interaction of the CAMs with the Leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules are not likely to be satisfactory for therapeutic use.
It follows that small molecules having the similar ability as large protein molecules to directly and selectively antagonize the binding of the CAMs to the Leukointegrins would make preferable therapeutic agents. WO9839303 discloses a class of small molecule inhibitors of the interaction of LFA-1 and ICAM-1. WO9911258 discloses that the fungal metabolite mevinolin and derivatives bind to LFA-1 and disrupt the interaction of LFA-1 and ICAM-1.
A first aspect of the invention comprises a method for treating or preventing inflammatory and immune cell-mediated diseases by the administration of certain novel small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a). A second aspect of the invention comprises novel small molecules having the above-noted therapeutic activities. A third aspect of the invention comprises methods for making these novel compounds. A final aspect of the invention comprises pharmaceutical compositions comprising the above-mentioned compounds suitable for the prevention or treatment of inflammatory and immune cell-mediated conditions.
The invention comprises compounds of the formula I 
wherein:
Y is an oxygen or sulfur atom;
Z is an oxygen or sulfur atom;
X is a divalent group of the formula  greater than CHR1,  greater than NR1,  greater than CHSO2R1, or  greater than NSO2R1, or an oxygen or sulfur atom,
wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) halogen,
(ii) oxo,
(iii) aryl, which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR7, wherein R7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR8R9, wherein R8 and R9 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R8 and R9 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR10R11, wherein R10 and R11 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R10 and R11 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR12b, wherein R12b is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R13, R14 and R15 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94COOR16, wherein R16 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) cyano,
(vi) a group of the formula xe2x80x94CONR17R18, wherein R17 and R18 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R17 and R18 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(viii) a group of the formula xe2x80x94SR20, wherein R20 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94NR21R22, wherein R21 and R22 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR23, wherein n is 0, 1 or 2, wherein R23 is straight or branched allyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R21 and R22 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) a quaternary group of the formula 
xe2x80x83wherein R24, R25 and R26 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R27, R28 and R29 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and
xe2x80x83R30, R31, R32 and R33 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R30, R31, R32 and R33 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) a carboxylic ester group of 2 to 7 carbon atoms,
(iii) a carboxylic acid group of 2 to 5 carbon atoms,
(iv) a phosphonic acid group of 1 to 6 carbon atoms, or
(v) a sulfonic acid groups of 1 to 6 carbon atoms, or
(I) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR7, wherein R7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR8R9, wherein R8 and R9 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R8 and R9 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR10R11, wherein R10 and R11 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R10 and R11 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR12b, wherein R12b is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano, or
(xi) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R13, R14 and R15 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring;
R2 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR34, wherein R34 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(ii) a group of the formula xe2x80x94NR35R36, wherein R35 and R36 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms;
R3 is a group of the formula xe2x80x94(CR37R38)x(CR39R40)yR41, wherein;
xe2x80x83x and y are each independently 0 or 1,
xe2x80x83R37, R38 and R39 are each, independently:
(A) a hydrogen atom,
(B) a group of the formula xe2x80x94OR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
xe2x80x83R40 is:
(A) a hydrogen atom,
(B) a group of the formula xe2x80x94OR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, or
(D) aryl which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) R43, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR44, wherein R44 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR45R46, wherein R45 and R46 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or
xe2x80x83wherein R45 and R46 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR47R48, wherein R47 and R48 are each independently a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R47 and R48 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR49, wherein R49is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR50, wherein R50 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano,
(k) nitro,
(l) an amidino group of the formula 
xe2x80x83wherein R51, R52 and R53 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and
xe2x80x83wherein two of R51, R52 and R53 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or
(m) halogen,
(ii) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R43,
(iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(iv) a group of the formula xe2x80x94COOR54, wherein R54 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(v) a group of the formula xe2x80x94NR55R56, wherein R55 and R56 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R55 and R56 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R55 and R56 may additionally be the group R43,
(vi) a group of the formula xe2x80x94CONR57R58, wherein R57 and R58 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R57 and R58 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R57 and R58 may additionally be the group R43,
(vii) a group of the formula xe2x80x94COR59, wherein R59 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R43,
(viii) a group of the formula xe2x80x94OR60, wherein R60 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R43,
(ix) a group of the formula xe2x80x94SR61, wherein R61 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R43,
(x) cyano,
(xi) nitro, or
(xii) halogen,
xe2x80x83R41 is:
xe2x80x83aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR63, wherein R63 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or
xe2x80x83wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R66 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano,
(xi) nitro, or
(xii) an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or
(xiii) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R62,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR73, wherein R73 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR74R75, wherein R74 and R75 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R74 and R75 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R74 and R75 may additionally be the group R62,
(F) a group of the formula xe2x80x94CONR76R77, wherein R76 and R77 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R76 and R77 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R76 and R77 may additionally be the group R62,
(G) a group of the formula xe2x80x94COR78, wherein R78 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R62,
(H) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R62,
(I) a group of the formula xe2x80x94SR80, wherein R80 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R62,
(J) cyano,
(K) nitro, or
(L) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Preferred are compounds of the formula I
wherein:
Y is an oxygen or sulfur atom;
Z is an oxygen or sulfur atom;
X is a divalent group of the formula  greater than CHR1,  greater than NR1,  greater than CHSO2R1, or  greater than NSO2R1, or an oxygen or sulfur atom,
xe2x80x83wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be monosubstituted with:
(i) halogen,
(ii) oxo,
(iii) aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR7, wherein R7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR8R9, wherein R8 and R9 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R8 and R9 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR10R11, wherein R10 and R11 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or
xe2x80x83wherein R10 and R 11 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR12b, wherein R12b is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R13, R14 and R15 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94COOR16, wherein R16 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) cyano,
(vi) a group of the formula xe2x80x94CONR17R18, wherein R17 and R18 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R17 and R18 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(viii) a group of the formula xe2x80x94SR20, wherein R20 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94NR21R22, wherein R21 and R22 are each, independently:
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR23, wherein n is 0, 1 or 2, wherein R23 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R21 and R22 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) a quatemary group of the formula 
xe2x80x83wherein R24, R25 and R26 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R27, R28 and R29 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and
xe2x80x83R30, R31, R32 and R33 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R30, R31, R32 and R33 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or
(H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) a carboxylic ester group of 2 to 7 carbon atoms,
(iii) a carboxylic acid group of 2 to 5 carbon atoms,
(iv) a phosphonic acid group of 1 to 6 carbon atoms, or
(v) a sulfonic acid group of 1 to 6 carbon atoms;
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein:
xe2x80x83R41 is:
xe2x80x83aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR63, wherein R63 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or
xe2x80x83wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R66 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano,
(xi) nitro,
(xii) an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring, or
(xiii) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R62,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR73, wherein R73 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR74R75, wherein R74 and R75 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R74 and R75 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R74 and R75 may additionally be the group R62,
(F) a group of the formula xe2x80x94CONR76R77, wherein R76 and R77 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R76 and R77 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R76 and R77 may additionally be the group R62,
(G) a group of the formula xe2x80x94COR78, wherein R78 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R62,
(H) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R62,
(I) a group of the formula xe2x80x94SR80, wherein R80 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R62,
(J) cyano,
(K) nitro, or
(L) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
More preferred are compounds of the formula I
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than CHR1 or  greater than NR1,
xe2x80x83wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be monosubstituted with:
(i) oxo,
(ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR7, wherein R7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NH2,
(g) a group of the formula xe2x80x94CONH2,
(h) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom or a methyl,
(i) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each hydrogen atoms, a group of the formula xe2x80x94COOR1 6, wherein R16 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(k) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(l) a quaternary group of the formula 
xe2x80x83wherein R24, R25 and R26 are each methyl and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each hydrogen atoms,
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6,
R30, R31, R32 and R33 are each hydrogen atoms, or
(H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) a carboxylic ester group of 2 to 7 carbon atoms,
(iii) a carboxylic acid group of 2 to 5 carbon atoms,
(iv) a phosphonic acid group of 1 to 6 carbon atoms, or
(v) a sulfonic acid group of 1 to 6 carbon atoms;
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR63, wherein R63 is methyl,
(vi) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom or methyl,
(vii) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom or methyl,
(viii) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom or methyl,
(ix) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom or methyl,
(x) cyano,
(xi) nitro, or
(xii) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms and which additionally may be monosubstituted with R62,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR73, wherein R73 is methyl,
(E) a group of the formula xe2x80x94NR74R75, wherein R74 and R75 are each, independently, a hydrogen atom or methyl, and
xe2x80x83wherein one of R74 and R75 may additionally be the group R62,
(F) a group of the formula xe2x80x94CONR76R77, wherein R76 and R77 are each, independently, a hydrogen atom or methyl, and
xe2x80x83wherein one of R76 and R77 may additionally be the group R62,
(G) a group of the formula xe2x80x94COR78, wherein R78 is a hydrogen atom, methyl or R62,
(H) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, methyl or R62,
(I) a group of the formula xe2x80x94SR80, wherein R80 is a hydrogen atom, methyl or R62,
(J) cyano,
(K) nitro, or
(L) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Even more preferred are compounds of the formula I:
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than CHR1 or  greater than NR1,
xe2x80x83wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be monosubstituted with:
(i) oxo,
(ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR7, wherein R7 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NH2,
(g) a group of the formula xe2x80x94CONH2,
(h) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom or a methyl,
(i) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each hydrogen atoms,
(j) a group of the formula xe2x80x94COOR16, wherein R16 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(k) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(l) a quaternary group of the formula 
xe2x80x83wherein R24, R25 and R26 are each methyl and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each hydrogen atoms,
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6,
xe2x80x83R30, R31, R32 and R33 are each hydrogen atoms, or
(H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) a carboxylic ester group of 2 to 7 carbon atoms,
(iii) a carboxylic acid group of 2 to 5 carbon atoms,
(iv) a phosphonic acid group of 1 to 6 carbon atoms, or
(v) a sulfonic acid group of 1 to 6 carbon atoms;
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, and pyrazinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, and pyrazinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) xe2x80x94COOH,
(iii) a group of the formula xe2x80x94COOR63, wherein R63 is methyl,
(iv) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom or methyl, or
(v) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms or which may be monosubstituted with R62,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR73, wherein R73 is methyl,
(E) a group of the formula xe2x80x94CONR76R77, wherein R76 and R77 are each methyl, and wherein one of R76 and R77 is methyl and the other is the group R62,
(F) a group of the formula xe2x80x94COR78, wherein R78 is a hydrogen atom, methyl or R62,
(G) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, methyl or R62,
(H) cyano,
(I) nitro, or
(J) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Still more preferred are compounds of the formula I
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than CHR1 or  greater than NR1,
xe2x80x83wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be monosubstituted with:
(i) oxo,
(ii) aryl selected from the class consisting of phenyl or pyridyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom or a methyl,
(f) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each hydrogen atoms,
(iii) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(iv) a quaternary group of the formula 
xe2x80x83wherein R24, R25 and R26 are each methyl and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each hydrogen atoms,
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6,
xe2x80x83R30, R31, R32 and R33 are each hydrogen atoms, or
(H) piperidyl, wherein the nitrogen atom of said group is optionally substituted with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) a carboxylic ester group of 2 to 7 carbon atoms,
(iii) a carboxylic acid group of 2 to 5 carbon atoms,
(iv) a phosphonic acid group of 1 to 6 carbon atoms, or
(v) a sulfonic acid group of 1 to 6 carbon atoms;
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83aryl selected from the class consisting of phenyl or pyridyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, or pyridyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) xe2x80x94COOH
(iii) a group of the formula xe2x80x94COOR63, wherein R63 is methyl,
(iv) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom or methyl, or
(v) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms or which may be monosubstituted with R62,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with fluorine or oxo,
(D) a group of the formula xe2x80x94COOR73, wherein R73 is methyl,
(E) a group of the formula xe2x80x94CONR76R77, wherein R76 and R77 are each methyl, and wherein one of R76 and R77 is methyl and the other is the group R62,
(F) a group of the formula xe2x80x94COR78, wherein R78 is a hydrogen atom, methyl or R62,
(G) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, methyl or R62,
(H) cyano,
(I) nitro, or
(J) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof
Especially preferred are compounds of the formula I
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than CHR1 or  greater than NR1,
xe2x80x83R1 is:
(A) a hydrogen atom,
(B) alkyl of 1 to 2 carbon atoms which may be monosubstituted with:
(i) oxo,
(ii) aryl selected from the class consisting of phenyl or pyridyl,
xe2x80x83wherein one hydrogen atom of said aryl group may be optionally replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94OR12a, wherein R12a is a hydrogen atom or a methyl, or
(f) an amidino group of the formula 
xe2x80x83wherein R13, R14 and R15 are each hydrogen atoms, or
(iii) a group of the formula xe2x80x94OR19, wherein R19 is a hydrogen atom or methyl,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
xe2x80x83R27, R28 and R29 are each hydrogen atoms, or
(G) an guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6,
xe2x80x83R30, R31, R32 and R33 are each hydrogen atoms,
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83phenyl
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, or pyridyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) a group of the formula xe2x80x94COOR63, wherein R63 is methyl,
(iii) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom or methyl, or
(iv) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms or which may be monosubstituted with R62,
(C) a group of the formula xe2x80x94COOR73, wherein R73 is methyl,
(D) a group of the formula xe2x80x94COR78, wherein R78 is methyl or R62,
(E) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, methyl or R62,
(F) cyano,
(G) nitro, or
(H) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Even more especially preferred are compounds of the formula I
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than NR1,
xe2x80x83R1 is:
(A) a hydrogen atom,
(B) methyl or ethyl, or
(C) xe2x80x94COCH3 
R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83phenyl
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, or pyridyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) a group of the formula xe2x80x94COOR63, wherein R63 is methyl,
(iii) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom or methyl, or
(iv) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms or which may be monosubstituted with R62,
(C) a group of the formula xe2x80x94COOR73, wherein R73 is methyl,
(D) a group of the formula xe2x80x94COR78, wherein R78 is methyl or R62,
(E) a group of the formula xe2x80x94OR79, wherein R79 is a hydrogen atom, methyl or R62,
(F) cyano,
(G) nitro, or
(H) halogen;
R4 is Cl or trifluoromethyl;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Penultimately preferred are compounds of the formula I
wherein:
Y is an oxygen atom;
Z is an oxygen atom;
X is a divalent group of the formula  greater than NR1,
xe2x80x83R1 is:
(A) a hydrogen atom,
(B) methyl or ethyl, or
(C) xe2x80x94COCH3 
xe2x80x83R2 is:
(A) a hydrogen atom, or
(B) methyl;
R3 is a group of the formula xe2x80x94CH2R41, wherein
xe2x80x83R41 is
xe2x80x83phenyl
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group are necessarily and independently replaced with:
(A) R62, which is aryl selected from the class consisting of phenyl, or pyridyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl, or
(ii) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms,
(C) a group of the formula xe2x80x94COR78, wherein R78 is methyl or R62,
(D) halogen;
R4 is a chlorine atom;
R5 is a hydrogen atom; and,
R6 is CN or NO2;
and pharmaceutically acceptable salts thereof.
Ultimately preferred are the following compounds of the formula I:
5-(R)-(4-bromobenzyl)-3 -(3-chloro-5-nitrophenyl)-5-methylimidazoline-2,4-dione; and,
5-(R)-(4-bromobenzyl)-3 -(3 -chloro-5 -cyanophenyl)-5-methylimidazoline-2,4-dione;
and pharmaceutically acceptable salts thereof.
It will be appreciated that the compounds of the formula I have at least one chiral center. Most preferred are those compounds of formula I with the absolute stereochemistry depicted below in formula Ia. 
Compounds of the invention may be prepared by the general methods described below. Typically, reaction progress may be monitored by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature.
Intermediates used in the preparation of the compounds of formula I may be prepared by the method described below and outlined in Scheme I. 
The isocyanate derivative of the appropriate amino acid (III) is reacted with the desired aniline (IV) in a suitable solvent such as THF plus HMPA, in the presence of a suitable base, such as potassium bis(trimethylsilyl)amide Following workup, consisting of washing with aqueous acid, such as aqueous ammonium chloride followed by purification, for example by silica gel chromatography or recrystallization, the desired Ib is obtained.
If the thiocarbonyl is desired, several reagents are known in the literature which will convert carbonyls to thio carbonyls. A typical sequence involves heating the substrate with a reagent such as P2S3 in a high boiling solvent such as tetralin for between 1 and 48 hr. Isolation of the product follows relatively standard conditions such as the dilution of the mixture into an organic solvent such as EtOAc and washing this mixture with water and saturated aqueous NaCl followed by drying and concentration. Purification is accomplished by silica gel chromatography or recrystallization, to afford Ic.
This compound can be selectively hydrolyzed to the desired monothiocarbonyl compound depending on the choice of conditions. In general the thiocarbonyl at the 4-position of the ring is more susceptible to nucleophilic conditions. It can be converted to the 4-oxo-species (Id) by treatment with aqueous ethanolamine followed by acid hydrolysis Purification is easily performed by silica gel chromatography or recrystallization.
Alternatively, the isothiocyanate derivative of the methyl or ethyl ester of III may be reacted with IV in a suitable solvent, such as 1,4-dioxane, under an inert atmosphere at about 50-100xc2x0 C. for about 1-24 hr to provide Id. If one uses the racemic III or ester of III, the product is racemic at the asymmetric carbon. By starting with a single enantiomer of III or ester of III, one obtains the single enantiomer of Id.
The starting amino acids and their derivatives necessary for the synthesis of the hydantoin and thio-hydantoin structures are either commercially available or are produced by obvious modifications of known literature procedures (see e.g.: Williams, R. W. Synthesis of Optically Activexcex1-Amino Acids; Pergamon: Oxford, 1989, xcex1-Amino Acid Synthesis; O""Donnell, M. J., Ed.; Tetrahedron Symposium in Print; Pergamon: London, 1988: Vol. 44, Issue 17, Jung, M. J. Chemistry and Biochemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: New York, 1985; p.227, and Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61: 7398-7401). The synthesis and resolution of ethyl 2-amino-2-(4-bromobenzyl)-propanoate is given by way of example.
A solution of alanine ethyl ester hydrochloride (15.3 g, 99.3 mmol) in 60 mL of water was treated with triethylamine (14.6 mL, 104.8 mmol) at room temperature for 30 min. The mixture was then extracted twice with 100 mL of methylene chloride. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to afford 10.0 g of the free base of the amino ester (86% yield). The residue was re-dissolved in methylene chloride and cooled in an ice bath. Magnesium sulfate (11.3 g, 93.9 mmol) was added, followed by trimethyl acetaldehyde (9.3 mL, 85.6 mmol). The ice bath was removed, and the mixture was stirred overnight. The magnesium sulfate was removed by filtration, and the filtrate was concentrated in vacuo to afford 11.8 g of the imine intermediate (74.6% yield).
The imine from above (11.8 g, 63.7 mmol) was dissolved in toluene (90 mL). 4-bromobenzyl bromide (17.5 g, 70.1 mmol) was added, and the reaction was cooled to about xe2x88x9210xc2x0 C. Potassium tert-butoxide (8.6 g, 76.5 mmol) was added at such a rate that the temperature did not exceed 0xc2x0 C. The reaction stirred in the cold bath for two hours, then was diluted with ether and washed with water (150 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to afford a clear yellow oil. This was treated with 1 N HCl (100 ml, 100 mmol) and stirred overnight. The reaction was extracted with ethyl acetate (100 mL), and the aqueous layer was to afford 14.1 g of the racemic amino ester hydrochloride (68.7% yield). Isocyanate derivatives can be made by reacting the aminoacid ester with a phosgene equivalent such as trichloromethyl chloroformate. This is exemplified in the Synthetic Examples below.
The racemic compounds can be resolved into their component enantiomers via a number of known techniques. Ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate was produced from racemic ethyl 2-amino-2-(4-bromobenzyl)-propanoate by the following procedure: To 1.3 L of a buffer made from 13.69 g KH2PO4 and 2 L of water was added 20 g of the commercially available enzyme Lipase L10 (Amano Enzyme USA Co., Ltd, Lombardi, Ill.) followed by 12 g of the HCl salt of the racemic amino ester. The pH was monitored and 1 N KOH was added as needed to keep the pH of the mixture at 6.4. The course of the reaction was monitored with reverse phase HPLC and after 2 days, the HPLC analysis indicated that 50.4% of the starting material had been hydrolyzed. At this point enough solid NaHCO3 was added to adjust the pH to 8.1 and the mixture was extracted twice with toluene, ether and EtOAc. The combined organic layers was dried and concentrated and the crude product purified by silica gel chromatography (EtOAC: Hexanes) to yield 5.21 g (87%) of ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate. Modifications to the above procedures and further transformations of initial products to obtain additional compounds of the invention are known to those skilled in the art and are analogous to those described in WO 9839303.